1. Expert guide to universe of choice after metformin – An evidence based approach
Dr. A. K. Singh
M.D (Medicine), D.M (Endocrinology)
Consultant Endocrinologist
G D Hospital & Diabetes Institute, Kolkata

3. Medicine Update
Vol. 24;
2014

6. Choice after metformin failure...
Pioglitazone
AGI
QR Bromo
SUs
DPP4 Inhibitors
SGLT 2 Inhibitors
GLP-1 Analogues
Basal/premix Insulin
How to answer this in evidence based era..?
SUs vs DPP4I
SUs vs SGLT2I
DPP4I vs SGLT2I

7. Sulfonylureas – lessons learnt so far...
Advantage
Disadvantage
Time tested – Since 1950
Robust glucose reduction in early stage
Inexpensive
RCT did’nt give bad CV signals
“Gluco-centric “ without “Disease-centric” properties
Durability – less (ADOPT)
Hypoglycemia – major issue
Weight gain
Possible beta cell apoptosis
? Prevents ischemic preconditioning (Glibenclamide)
Observational studies and meta-analysis shows increasingly bad CV signals
Singh AK. Indian J Endocr Metab 2014;18:617-23

8. Gliptins – lessons learnt so far...
Advantage
Disadvantage
A1c reduction at par with Met, SUs and SGLT-2I
Minimal hypoglycaemia with
weight neutrality or loss
Possible pleiotropic benefit and beta cell protection
Pancreatitis : not a great concern
Bone friendly
Meta-analysis of pooled data from phase 2/3 showed CV benefit
RCT – TECOS, SAVOR TIMI & EXAMINE suggested CV neutrality
Cost
Possible off-target side effect
Signals of higher CV mortality with VILDA in VIVIDD trial
Increased heart failure hospitalisation with SAXA in SAVOR TIMI - ? Play of chance
Arthritis - FDA
Singh AK. Indian J Endocr Metab 2014;18:617-23

9. SGLT2I: Lessons learnt so far...
Advantage
Disadvantage
A1c reduction at par with metformin, SU, Gliptins
Durability seems superior to SU
Wt loss superior to metformin and gliptins
BP reduction robust than metformin and gliptins
Robust reduction in CV death, hHF, all-cause mortality in EMPA-REG
Genital and urinary infection
Volume depletion with loop diuretics
Postural hypotension with RAAB and diuretics
Safety in elderly >75 yr
Loosing effectiveness in renal insufficiency
Bone health : ↑ PTH (fractures with Cana)
EuDKA – very rare
Singh AK. Indian J Endocr Metab, 2014;18:617-23

10. Increases (Tolbutamide)
SUs and CV outcome
Study comparison
Impact on total/CV mortality
UGDP
Increases (Tolbutamide)
UKPDS
No Difference
RECORD
No Difference
ADOPT
No Difference
ACCORD
No Difference
ADVANCE
No Difference
VADT
No Difference
ORIGIN
No Difference

11. Where is the difficulty with SUs?
To date, the large CV outcome trials have essentially assessed the impact of multiple combinations of glucose-lowering agents as part of an overall treatment regimen of intensive vs. conventional
(e.g. UKPDS, ACCORD, ADVANCE & VADT, ORIGIN)
Thus, a comparative understanding of the CV impact of the most widely used diabetes drugs is actually lacking.
Discordantly, data from observational studies finds increased mortality with SUs.

12. Glipizide had intermediate risk Glibenclamide has worst outcome
SUs and CV outcome
Most neutral CV outcome data lies with Gliclazide followed by Glimepiride
Glipizide had intermediate risk
Glibenclamide has worst outcome
Singh AK. Expert Review of Clinical Pharmacology; 2016

13. Head-to-head study
SUs vs DPP4I
SUs vs SGLT2I
DPP4I vs SGLT2I

15. SUs vs Gliptins ( 12 Head-to-head studies) 12 Studies = 5 Sita, 4 Vilda, 1 Saxa, 1 Lina, 1 Alo (n=11000)
A1C reduction#
A1c <7%*
Hypoglycaemia
Weight gain
Adverse effect
CV events reduction
Beta cell effect
DPP4I produced less A1c reduction by 0.11%
9% less with DPP4I when trial <32 weeks
87% less with DPP4I
1.65 Kg less with DPP4I
21% less total adverse event with DPP4I
47% less with DPP4I
Better PI/I ratio & HOMA-IR with DPP4I
# DPP4I showed better efficacy when compared to 2nd gen SU and also in CKD patient
* Same % of patient had A1C <7% when trial >32 weeks
Zhang et al, Diabetes Metab Res Rev Oct 5.
Singh AK. IJEM, Sept-Oct 2014

16. CV Events: SU vs Gliptins (Met-analysis of head-to-head trials)
Study
(year)
Duration
(Week)
Drug
(dose)
CV Events (% of patients)
Arzona Ferreira et al, 2013
54 wk
Sitagliptin (25 mg)
7.8 %
Glipizide ( mg)
9.2 %
Filozof et al, 2010
52 wk
Vildagliptin (100 mg)
1.4 %
Gliclazide ( mg)
2.4 %
Gallwitz et al, 2012
104 wk
Linagliptin (5 mg)
1.5 %
Glimepiride (1-4 mg)
3.4 %
Rosenstock et al, 2013
Alogliptin (25 mg)
0.5 %
Glipizide (5-10 mg)
0.9 %
Singh AK. IJEM, Sept-Oct 2014
Zhang et al, Diabetes Metab Res Rev Oct 5. doi: /dmrr [Epub ahead of print]

17. SU vs Gliptins – CV outcome 12 head-to-head trials, 5 Sitagliptin, 4 Vildagliptin, 1 Saxagliptin, 1 Linagliptin, 1 Alogliptin (n=11000) 4 looked for CV outcome
47% less with DPP4I
Diabetes Metab Res Rev Oct 5. doi: /dmrr [Epub ahead of print]
Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulphonylureas----A meta-analysis from randomized clinical trials.
Zhang Y, Hong J, Chi J, Gu W, Ning G, Wang W.

18. Summary: SUs or DPP-4I?
SUs and DPP-4I are both insulinotropic, but with different mechanisms. SUs may cause (severe) hypoglycamia, whereas DPP-4I don‘t.
Whether SUs elicit cardio-vascular problems is still not known. By direct (head-to-head) comparison, DPP-4I are associated with less cardio-vascular events than SUs. Whether this indicates a harm of SUs or a benefit of DPP-4 inhibitors needs to be clarified from further CV outcome studies.
CAROLINA may answer or at least enlighten further.

20. Head-to-head study
SUs vs DPP4I
SUs vs SGLT2I
DPP4I vs SGLT2I

21. Singh AK. Indian J Endocr Metab 2014; 18(5): 617-623 (updated)

22. Apostolos et al, EASD Vienna 2013

23. Head-to-head study
SUs vs DPP4I
SUs vs SGLT2I
DPP4I vs SGLT2I

24. Singh AK. Indian J Endocr Metab 2014; 18(5): 617-623 (updated)

25. Apostolos et al, EASD Vienna 2013

26. Conclusion
Currently there is no compelling evidence to suggest that SUs (in particular gliclazide and possibly glimepiride) truely increases CV events. However, it is used primarily beacuse of its low cost. Nonetheless hypoglycemia is a major issue (least with gliclazide MR)
Because of their advantages (no hypoglycaemia and no weight gain) and CV neutrality (SITA most neutral) DPP-4I are increasingly used instead of SUs. Undoubtly , DPP-4I are preferble in DKD patients and elderly population over all oral agents.
SGLT-2I appears very encouraging in weight loss and BP reduction, apart from moderate efficacy. Robust outcome in EMPA-REG also gave great confidence in using this class as a whole. However, use in elderly and renal insuffiency is a great limitation. EuDKA is possible but rare. Pharmacovigilance is must.

27. Criteria for ideal oral drug after metformin...
Efficacy
Safety –
short term – hypoglycemia
long term – CV, All-cause, Cancer mortality
Durability
Good partner to insulin (eventually)
Corrects the pathogenesis of T2DM – desirable
Safe in co-morbid condition – DKD, CLD, IHD, CCF

28. THANKS